Abstract
Ethylmalonic encephalopathy is caused by mutations in ETHE1, a mitochondrial matrix sulfur dioxygenase, leading to failure to detoxify sulfide, a product of intestinal anaerobes and, in trace amounts, tissues. Metronidazole, a bactericide, or N-acetylcysteine, a precursor of sulfide-buffering glutathione, substantially prolonged the lifespan of Ethe1-deficient mice, with the combined treatment being additive. The same dual treatment caused marked clinical improvement in five affected children, with hardly any adverse or side effects.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Tiranti, V. et al. Nat. Med. 15, 200–205 (2009).
Szabó, C. Nat. Rev. Drug Discov. 6, 917–935 (2007).
Mancardi, D. et al. Biochim. Biophys. Acta 1787, 864–872 (2009).
Kang, S.S. et al. PLoS Med. 5, e41 (2008).
Marí, M., Morales, A., Colell, A., García-Ruiz, C. & Fernández-Checa, J.C. Antioxid. Redox Signal. 11, 2685–2700 (2009).
Hildebrandt, T.M. & Grieshaber, M.K. FEBS J. 275, 3352–3361 (2008).
Liu, J. et al. Nature 459, 387–392 (2009).
Whitehead, N.P., Pham, C., Gervasio, O.L. & Allen, D.G. J. Physiol. 586, 2003–2014 (2008).
Durham, W.J. et al. Cell 133, 53–65 (2008).
Atkuri, K.R., Mantovani, J.J., Herzenberg, L.A. & Herzenberg, L.A. Curr. Opin. Pharmacol. 7, 355–359 (2007).
Wredenberg, A. et al. Proc. Natl. Acad. Sci. USA 99, 15066–15071 (2002).
Sörensen, L. et al. J. Neurosci. 21, 8082–8090 (2001).
Mineri, R. et al. J. Med. Genet. 45, 473–478 (2008).
Tiranti, V. et al. Am. J. Hum. Genet. 74, 239–252 (2004).
Acknowledgements
This work was supported by the Pierfranco and Luisa Mariani Foundation Italy, Fondazione Telethon-Italy grant number GGP07019 and grant RF-INN-2007-634163 of the Italian Ministry of Health. We thank E. Lamantea for assistance in the preparation of figures and S. Ravaglia for help in statistical analyses.
Author information
Authors and Affiliations
Contributions
Study design: V.T. and M.Z.; clinical evaluation and sample collection: A.B.B. and I.D.; neuroradiological evaluation: M.S.; histochemical evaluation: C.L.; biochemical assays: A.B.B. and T.H.; mouse treatment and evaluation: C.V.; statistical analysis: C.V.; manuscript writing: M.Z.; critical revision of the manuscript: C.V., V.T. and M.Z.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–7 (PDF 685 kb)
Rights and permissions
About this article
Cite this article
Viscomi, C., Burlina, A., Dweikat, I. et al. Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy. Nat Med 16, 869–871 (2010). https://doi.org/10.1038/nm.2188
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm.2188
This article is cited by
-
Disruption of Bioenergetics in the Intestine of Wistar Rats Caused by Hydrogen Sulfide and Thiosulfate: A Potential Mechanism of Chronic Hemorrhagic Diarrhea in Ethylmalonic Encephalopathy
Cell Biochemistry and Biophysics (2023)
-
Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype
Neurological Sciences (2023)
-
AAV-vector based gene therapy for mitochondrial disease: progress and future perspectives
Orphanet Journal of Rare Diseases (2022)
-
Mitochondrial Dysfunction and Redox Homeostasis Impairment as Pathomechanisms of Brain Damage in Ethylmalonic Encephalopathy: Insights from Animal and Human Studies
Cellular and Molecular Neurobiology (2022)
-
Ethylmalonic encephalopathy and liver transplantation: long-term outcome of the first treated patient
Orphanet Journal of Rare Diseases (2021)
